Monascus fermentation enhances the lipid-lowering properties of ginseng in vivo and component assay.

Hyperlipidemia is a global health concern characterized by elevated lipid levels and increased cardiovascular risk. Ginseng (Panax ginseng) has lipid-lowering properties, and Monascus fermentation can yield monacolin K, a natural statin. However, it remains unclear whether Monascus-fermented ginseng (MFG) offers synergistic benefits over ginseng or Monascus alone. This study aimed to compare the lipid-lowering efficacy of MFG versus unfermented ginseng, Monascus, and their non-fermented combination in hyperlipidemic mice. Multi-omics analyses (hepatic transcriptomics, serum/fecal metabolomics, and gut microbiota profiling) were integrated to elucidate underlying mechanisms, and fecal microbiota transplantation (FMT) assessed the causal role of MFG-altered microbiota. MFG supplementation markedly improved serum lipid profiles and attenuated hepatic steatosis, outperforming ginseng, Monascus, or their unfermented combination. Phytochemical analysis confirmed that fermentation introduced monacolin K into MFG and increased its rare ginsenoside content, distinguishing it from unfermented ginseng. Mechanistically, MFG increased hepatic p-AMPK and upregulated fatty acid oxidation while downregulating lipogenesis (SREBP-1c, FAS). Metabolomics revealed elevated short-chain fatty acid levels and enhanced bile acid biotransformation in MFG-treated mice. MFG reshaped gut microbiota composition and enriched beneficial taxa. Importantly, FMT from MFG-fed donors recapitulated the lipid-lowering effects in recipients, confirming a microbiota-mediated mechanism. In conclusion, MFG exerts superior lipid-lowering effects through complementary host metabolic and gut microbial modulation, highlighting fermented herbal products as promising interventions against hyperlipidemia.